Choosing an Initial ART Regimen: Guidelines and Recommendations

Selecting an Initial ART Regimen www.hivguidelines.org AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program

Purpose of This Guideline Purpose of This Guideline Provide a clear and concise roadmap for clinicians to follow in choosing from among several equally efficacious ART regimens based on individual patient characteristics and preferences. Provide a list of ART regimens to avoid. Provide dosing considerations for individuals with renal or hepatic impairment and important drug-drug and food interactions. Encourage clinicians to seek the assistance of an experienced HIV care provider when treating patients with extensive comorbidities. Integrate current evidence-based clinical recommendations into the healthcare-related implementation strategies of the New York State Ending the Epidemic initiative. AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Recommendations: Recommendations: Regimen Selection Regimen Selection When selecting an initial ART regimen for treatment naive-patients, clinicians should: Perform genotypic HIV resistance testing results for protease (A2), reverse transcriptase (A2), and integrase (B2) genotypic resistance if the testing has not already been performed or results are not otherwise available. Inform patients of the regimen options and engage in shared decision-making to optimize the likelihood of adherence. (A3) Assess for comorbidities and chronic coadministered medications that may affect the choice of regimen for a patient s initial ART. (A3) Choose a preferred ART regimen unless one of the alternative regimens is a better choice based on individual patient factors. (A1) Recommend a single-tablet regimen or a regimen with once-daily dosing unless those regimens are contraindicated by HIV resistance, drug-drug interactions, intolerance, allergy, or access. (A2) Ask patients about their reproductive plans and discuss the use of contraception. (A3) AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Recommendations: Recommendations: Regimen Selection Regimen Selection, continued With the exception of DTG/3TC, clinicians should not prescribe 2-drug regimens as initial ART. (A3) Clinicians should prescribe DTG/3TC only after: HIV resistance and HBV status are known. (A1) Genotypic resistance testing results have confirmed that a patient does not have a major reverse transcriptase mutation, including the M184V/I resistance mutation. DTG/3TC is contraindicated in patients with these resistance-associated mutations. (A1) AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Recommendations: Recommendations: Expert Consultation Expert Consultation Clinicians should consult with an experienced HIV care provider when selecting an initial ART regimen for a patient who has: Baseline genotypic testing results indicating the need for an ART regimen other than the available preferred or alternative regimens. (A3) Extensive comorbidities, including metabolic complications and obesity; comedications; impaired renal function; HBV or hepatitis C virus coinfection; or active opportunistic infections. (B3) The NYSDOH Clinical Education Initiative (CEI) provides access to HIV specialists through their toll-free CEI Line: 1-866-637-2342. AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Recommendations: Recommendations: Follow Follow- -up up Clinicians or clinical support staff should follow up by telephone or other methods, preferably within 2 weeks after treatment initiation, to assess tolerance and adherence; adherence should be reinforced at regular intervals. (A3) Clinicians should obtain a viral load test within 4 weeks after ART initiation to assess initial response to therapy. (A3) AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Preferred Initial ART Regimens for Nonpregnant Preferred Initial ART Regimens for Nonpregnant Adults: Single Adults: Single- -Tablet Tablet Regimen Comments Initiate only in patients confirmed to be negative for HLA-B*5701, including when a rapid-start or test-and-treat initiation of ART occurs before baseline laboratory test results are available. Initiate only in patients with CrCl 30 mL/min. Consider underlying risk of coronary heart disease. Documented DTG resistance after initiation in treatment-naive patients is rare. Magnesium- or aluminum-containing antacids may be taken 2 hours before or 6 hours after DTG; calcium-containing antacids or iron supplements may be taken simultaneously if taken with food. ABC/3TC/DTG Triumeq (A1) Initiate only in patients with CrCl 30 mL/min. Do not use in patients with hepatitis B virus coinfection. Do not initiate before HIV resistance tests results are available. Do not initiate in patients with NRTI resistance, including the M184V/I mutation. Do not initiate in patients with baseline HIV RNA levels >500,000 copies/mL until additional study data are available. Documented DTG resistance after initiation in treatment-naive patients is rare. Magnesium- or aluminum-containing antacids may be taken 2 hours before or 6 hours after DTG; calcium-containing antacids or iron supplements may be taken simultaneously if taken with food. 3TC/DTG Dovato (A1) AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Preferred Initial ART Regimens for Nonpregnant Preferred Initial ART Regimens for Nonpregnant Adults: Single Adults: Single- -Tablet Tablet, continued Regimen Comments Initiate only in patients with CrCl 30 mL/min. Contains 25 mg of TAF, unboosted. Magnesium- or aluminum-containing antacids may be taken 2 hours before or 6 hours after BIC; calcium-containing antacids or iron supplements may be taken simultaneously if taken with food. Documented DTG resistance after initiation in treatment-naive patients is rare. TAF 25 mg/FTC/BIC Biktarvy (A1) AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Preferred Initial ART Regimens for Nonpregnant Preferred Initial ART Regimens for Nonpregnant Adults: Multi Adults: Multi- -Tablet With Once Tablet With Once- -Daily Dosing Daily Dosing Regimen Comments For TAF/FTC, initiate only in patients with CrCl 30 mL/min. Contains 25 mg of TAF, unboosted. For TDF/FTC, initiate only in patients with CrCl 50 mL/min. For TDF/FTC, consider bone mineral density. Magnesium- or aluminum-containing antacids may be taken 2 hours before or 6 hours after DTG; calcium-containing antacids or iron supplements may be taken simultaneously if taken with food. Documented DTG resistance after initiation in treatment-naive patients is rare. TAF 25 mg/FTC or TDF 300 mg/FTC and DTG Descovy or Truvada and Tivicay (A1) For TAF/FTC, initiate only in patients with CrCl 30 mL/min. Contains 25 mg of TAF, unboosted. For TDF/FTC, initiate only in patients with CrCl 50 mL/min. For TDF/FTC, consider bone mineral density. Administer as TAF/FTC or TDF/FTC once daily and RAL HD 1200 mg once daily, dosed as two 600 mg HD tablets. To date, no clinical trials have been conducted with TAF and RAL; data are based on bioequivalence pharmacokinetic studies. Magnesium- or aluminum-containing antacids are contraindicated; coadministration of calcium- containing antacids is not recommended with RAL HD. TAF 25 mg/FTC or TDF 300 mg/FTC and RAL HD Descovy or Truvada and Isentress HD (A2) AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Alternative Initial ART Regimens for Alternative Initial ART Regimens for Nonpregnant Adults: Single Nonpregnant Adults: Single- -Tablet Regimen Comments Tablet Initiate only in patients with CrCl 30 mL/min. Carefully consider drug-drug interactions with COBI. Contains 10 mg TAF, boosted. TAF 10 mg/FTC/DRV/COBI Symtuza (B2) Initiate onlyin patients confirmed to have a CD4 count 200 cells/mm3 and HIV RNA level <100,000 copies/mL. Avoid use of RPV in a rapid-start or test-and-treat regimen if a patient s viral load and CD4 count results are not available. Initiate only in patients with CrCl 30 mL/min. Use with caution in patients with depression or a history of suicidality. To date, no clinical trials have been conducted; data are based on bioequivalence pharmacokinetic studies of TAF compared with TDF. Contraindicated with proton pump inhibitors. Use H2-blockers with caution and separate dosing by 12 hours. Must take with food. Contains 25 mg of TAF, unboosted. TAF 25 mg/FTC/RPV Odefsey (B3) Initiate only in patients with CrCl 50 mL/min. Contraindicated when coadministered with drugs that are strong CYP3A enzyme inducers. Consider bone mineral density. TDF/3TC/DOR Delstrigo (B1) AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Alternative Initial ART Regimens for Nonpregnant Alternative Initial ART Regimens for Nonpregnant Adults: Multi Adults: Multi- -Tablet With Once Tablet With Once- -Daily Dosing Daily Dosing Regimen Comments Initiate only in patients confirmed to be negative for HLA-B*5701. When a rapid-start or test-and-treat initiation of ART occurs before baseline laboratory test results are available, avoid use of ABC until a patient s HLA-B*5701 test is confirmed negative. Consider underlying risk of coronary heart disease. Contraindicated when coadministered with drugs that are strong CYP3A enzyme inducers. Initiate only in patients with CrCl 30 mL/min. Contraindicated when coadministered with drugs that are strong CYP3A enzyme inducers. For TAF/FTC, initiate only in patients with CrCl 30 mL/min. For TDF/FTC, initiate only in patients with CrCl 50 mL/min. For TDF/FTC, consider bone mineral density. Administer as TAF/FTC or TDF/FTC once daily and RAL 400 mg twice daily. Magnesium- or aluminum-containing antacids are contraindicated; calcium-containing antacids are acceptable with RAL. ABC/3TC and DOR Epzicom and Pifeltro (B2) TAF 25 mg/FTC and DOR Descovy and Pifeltro (B2) TAF 25 mg/FTC or TDF 300 mg/FTC and RAL Descovy or Truvada and Isentress (B3) AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Other ART Regimens for Nonpregnant Adults: Other ART Regimens for Nonpregnant Adults: Single Single- -Tablet Tablet Regimen Comments Initiate only in patients with CrCl 50 mL/min. Use with caution in patients with depression or a history of suicidality. Consider bone mineral density. Initiate onlyin patients confirmed to have a CD4 count 200 cells/mm3 and HIV RNA level <100,000 copies/mL. Initiate only in patients with CrCl 50 mL/min. Use with caution in patients with depression or a history of suicidality. Contraindicated with PPIs. Use H2-blockers with caution and separate dosing by 12 hours. Must take with food. Consider bone mineral density. TDF/FTC/EFV Atripla (B1) TDF/FTC/RPV Complera (B1) AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Other ART Regimens for Nonpregnant Adults: Other ART Regimens for Nonpregnant Adults: Multi Multi- -Tablet With Once Tablet With Once- -Daily Dosing Daily Dosing Regimen Comments Initiate only in patients confirmed to be negative for HLA-B*5701. Initiate only in patients with viral load <100,000 copies/mL. Carefully consider drug-drug interactions with RTV. Consider underlying risk of coronary heart disease. In treatment-naive patients on boosted ATV, H2-blockers should be taken simultaneously with ATV/RTV and food. If simultaneous dosing with food is not possible, ATV/RTV should be taken at least 10 hours after the H2-blocker. H2-blocker doses should not exceed the equivalent of 40 mg famotidine twice daily for ART-naive patients or 20 mg famotidine twice daily for ART-experienced patients. Use no more than the equivalent of 20 mg of omeprazole with ATV; administer PPIs at least 12 hours before ATV/RTV. When combined with antacids, ATV should be given 2 hours before or 1 to 2 hours after antacids and buffered medications. Scleral icterus from benign hyperbilirubinemia may be a concern. ABC/3TC and ATV and RTV Epzicom and Reyataz and Norvir (C1) Initiate only in patients confirmed to be negative for HLA-B*5701. Carefully consider drug-drug interactions with COBI. Consider underlying risk of coronary heart disease. ABC/3TC and DRV/COBI Epzicom and Prezcobix (B3) AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Other ART Regimens for Nonpregnant Adults: Other ART Regimens for Nonpregnant Adults: Multi Multi- -Tablet With Once Tablet With Once- -Daily Dosing Daily Dosing, continued Regimen Comments Initiate only in patients confirmed to be negative for HLA-B*5701. Carefully consider drug-drug interactions with RTV. Consider underlying risk of coronary heart disease. ABC/3TC and DRV and RTV Epzicom and Prezista and Norvir (B2) Initiate only in patients confirmed to be negative for HLA-B*5701. Initiate only in patients with viral load <100,000 copies/mL. Use with caution in patients with depression or a history of suicidality. Consider underlying risk of coronary heart disease. ABC/3TC and EFV Epzicom and Sustiva (C1) Initiate only in patients with CrCl 50 mL/min. Use with caution in patients with depression or a history of suicidality. Contains 25 mg of TAF, unboosted. TAF 25 mg/FTC and EFV Descovy and Sustiva (B3) Initiate only in patients confirmed to be negative for HLA-B*5701. Consider underlying risk of coronary heart disease. Administer as ABC/3TC once daily and RAL HD 1200 mg once daily, dosed as two 600 mg HD tablets. Magnesium- or aluminum-containing antacids are contraindicated; coadministration of calcium-containing antacids is not recommended with RAL HD. ABC/3TC and RAL HD Epzicom and Isentress HD (B3) AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Other ART Regimens for Nonpregnant Adults: Other ART Regimens for Nonpregnant Adults: Multi Multi- -Tablet With Twice Tablet With Twice- -Daily Dosing Daily Dosing Regimen Comments Initiate only in patients with CrCl 50 mL/min. Consider bone mineral density. TDF/FTC once daily and RAL 400 mg twice daily. Magnesium- or aluminum-containing antacids are contraindicated; calcium- containing antacids are acceptable with RAL. Initiate only in patients confirmed to be negative for HLA-B*5701. Consider underlying risk of coronary heart disease. Administer as ABC/3TC once daily and RAL 400 mg twice daily. Magnesium- or aluminum-containing antacids are contraindicated; calcium- containing antacids are acceptable with RAL. TDF/FTC and RAL Truvada and Isentress (B1) ABC/3TC and RAL Epzicom and Isentress (B1) AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Substitutions Substitutions In all cases, FTC and 3TC are interchangeable. TAF 10 mg and TAF 25 mg are not interchangeable. COBI and RTV should not be considered interchangeable because of their drug-interaction profiles. AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

ARVs to Avoid in Initial Therapy for ARVs to Avoid in Initial Therapy for Nonpregnant Adults Nonpregnant Adults ARV Comments NVP (Viramune) Life-threatening rash: Stevens-Johnson syndrome and toxic epidermal necrolysis are possible. d4T (Zerit); ddI (Videx) Serious toxicities: Potentially fatal lactic acidosis, peripheral neuropathy, pancreatitis, lipoatrophy, and hepatic steatosis are possible. DLV (Rescriptor) Thrice-daily dosing and inferior efficacy. ETR (Intelence) ETR does not have an FDA indication in ART-naive patients. MVC (Selzentry); NRTI-only regimens, either triple or quadruple Inferior efficacy and durability. ZDV (Retrovir) Not well tolerated because of bone marrow suppression (notably anemia), headache, and myopathies. Unboosted PIs Inferior efficacy relative to boosted PIs. FPV (Lexiva); IDV (Crixivan); TPV (Aptivus); NFV(Viracept) Either not well-studied or limited by dosing and side effects relative to recommended PIs. AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Selected Drug Selected Drug- -Drug Interactions to Drug Interactions to Discuss Before Initiating ART Discuss Before Initiating ART Drugs ARV(s): Comments H2-blockers ATV: In treatment-naive patients on boosted ATV, H2-blockers should be taken simultaneously with ATV/RTV with food. If simultaneous dosing with food is not possible, ATV/RTV should be taken at least 10 hours after the H2-blocker. H2-blocker doses should not exceed the equivalent of 40 mg famotidine twice daily for ART-naive patients or 20 mg famotidine twice daily for ART-experienced patients. RPV: Use with caution; administer H2-blockers at least 12 hours before or at least 4 hours after RPV. Inhaled steroids; statins COBI; RTV: Alternatives or dose adjustments may be needed. Consult the package inserts for drug-drug interactions between specific statins and ARVs. Polyvalent cations BIC; DTG: Take 2 hours before or 6 hours after DTG; calcium-containing antacids or iron supplements may be taken simultaneously if taken with food. RAL: Magnesium- or aluminum-containing antacids are contraindicated; calcium- containing antacids are acceptable. RAL HD: Magnesium- or aluminum-containing antacids are contraindicated; coadministration of calcium-containing antacids is not recommended. EVG: Separate dosing by 2 hours, either before or after dose of EVG. AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Selected Drug Selected Drug- -Drug Interactions to Drug Interactions to Discuss Before Initiating ART Discuss Before Initiating ART, continued Drugs ARV(s): Comments ATV: Contraindicated with ATV in treatment-experienced patients; in treatment-naive patients, use no more than equivalent of 20 mg of omeprazole with ATV, separated by 12 hours. RPV: Contraindicated. DTG: Metformin levels are significantly raised when coadministered with DTG. If used concomitantly, total daily dose of metformin should not exceed 1,000 mg without clinical evaluation of efficacy and adverse events. ATV/COBI; DRV/COBI; DRV/RTV; EFV: Use alternative or additional (e.g., barrier) contraceptive methods or choose alternative ART regimen. ATV; ATV/RTV: Use with caution; see manufacturer s package insert for specific dosing information. Proton pump inhibitors Metformin Ethinyl estradiol and norethindrone AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Selected Drug Selected Drug- -Drug Interactions to Drug Interactions to Discuss Before Initiating ART Discuss Before Initiating ART, continued Drugs ARV(s): Comments COBI; RTV: Apixaban: Reduce dose by 50% if patient is on 5 mg twice daily; avoid use if the indicated dose is 2.5 mg twice daily (based on age, weight, creatinine level). Dabigatran: No adjustment needed if CrCl 50 mL/min; avoid if CrCl <50 mL/min. Rivaroxaban: Avoid use. COBI; RTV: Clopidogrel: Avoid use. Prasugrel: No adjustment needed. Ticagrelor: Avoid use. Factor Xa inhibitors Platelet inhibitors AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Food Requirements Food Requirements Take With or Without Food 3TC ABC DOR DTG FTC RAL TAF TDF DTG/3TC TAF/FTC/BIC TAF/FTC/DOR Take With Food ATV/COBI ATV/RTV DRV/COBI DRV/RTV EVG RPV TAF/FTC/EVG/COBI TAF/FTC/DRV/COBI Take on Empty Stomach EFV AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Key Points Key Points General Principles in Choosing an Initial ART Regimen INSTI-based regimens are generally the best choice for most individuals because of tolerability and durability. Mental Health and Substance Use Neither mental health nor substance use disorders are contraindications to initiating ART. In some special cases, delay of initiation (for as short a time as possible) may be appropriate while addressing adherence issues and possible interactions (see the NYSDOH AI guideline Rapid ART Initiation). AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Key Points: Key Points: Special Considerations for Comorbid Conditions Special Considerations for Comorbid Conditions Both COBI and DTG can cause decreased tubular excretion of creatinine and may cause a slight increase in measured creatinine. ABC has been associated with a higher risk of myocardial infarction in some studies, although not in others. No clear causal link has been established. Boosted PIs and COBI-boosted EVG are associated with a higher incidence of hyperlipidemia than unboosted INSTIs. Consultation with an experienced HIV care provider is advised when a patient s baseline viral load is very high (HIV RNA level >750,000 copies/mL). AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

Key Points: Key Points: ART ART- -Initiation Laboratory Testing Initiation Laboratory Testing When initiating ART at the time of HIV diagnosis ( rapid start ), it is not necessary to have the results of baseline laboratory tests immediately available. Laboratory tests, as indicated below, should be ordered at the time of initiation of ART, and any necessary adjustments to therapy should be made as soon as the results are available (such as for renal function or evidence of resistance). ABC-containing regimens should not be used for rapid start without a documented negative HLA-B*5701 test result. AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

ART Regimens That are Not Recommended ART Regimens That are Not Recommended Based on Routine Baseline Laboratory Parameters Based on Routine Baseline Laboratory Parameters Laboratory Parameter ART Regimens That Are Not Recommended ABC/3TC (Epzicom) ABC/3TC/DTG (Triumeq) TDF/3TC/DOR (Delstrigo) TDF/FTC/EFV (Atripla) TDF/FTC/RPV (Complera) TAF/FTC (Descovy) TAF/FTC/BIC (Biktarvy) TAF/FTC/DRV/COBI (Symtuza) TAF/FTC/EVG/COBI (Genvoya) TAF/FTC/RPV (Odefsey) TDF/FTC (Truvada) DTG/3TC (Dovato) Laboratory Parameter ART Regimens That Are Not Recommended ABC/3TC and ATV/COBI (Epzicom and Evotaz) ABC/3TC and EFV (Epzicom and Sustiva) ABC/3TC and ATV and RTV (Epzicom and Reyataz and Norvir) TAF/FTC/RPV (Odefsey) TDF/FTC/RPV (Complera) TAF/FTC/RPV (Odefsey) TDF/FTC/RPV (Complera) CrCl <50 mL/min HIV RNA level 100,000 copies/mL CrCl <30 mL/min CD4 count <200 cells/mm3 AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

ARV Dose Adjustments for ARV Dose Adjustments for Hepatic or Renal Impairment Hepatic or Renal Impairment See full guideline for recommended dose adjustments for use of selected fixed-dose combination antiretroviral medications in patients with hepatic or renal impairment. AUGUST 2022 NYSDOH AIDS Institute Clinical Guidelines Program www.hivguidelines.org

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